Biodisintegrable medical devices

ABSTRACT

The present disclosure relates to medical devices which contain one or more polymeric regions that are at least partially biodisintegrable in bodily fluid. These devices may be implanted or inserted into a subject for treatment of various diseases, disorders and conditions. The present disclosure further provides methods of slowing and/or accelerating the dissolution of such medical devices by administering a composition which alters the pH of the subject&#39;s urine.

STATEMENT OF RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/546,290, filed Jul. 11, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/327,905, filed Dec. 4, 2008, now U.S. Pat. No.8,241,657, entitled “Biodisintegrable Medical Devices” which claims thebenefit of U.S. Provisional Patent Application Ser. No. 61/005,287,filed Dec. 4, 2007, entitled “Biodisintegrable Medical Devices.” Each ofthese applications is incorporated by reference herein in its entirety.

Field of the Invention

The present invention relates generally to medical devices, and moreparticularly to medical devices that contain one or more polymericregions that are at least partially biodisintegrable in bodily fluid.

BACKGROUND OF THE INVENTION

Pain or irritation associated with medical devices of the urinary tractis a major concern in modern urology. As a specific example,kidney-ureter-bladder (KUB) devices such as ureteral stents are widelyused to facilitate drainage in the upper urinary tract (e.g., from thekidney to the bladder).

For example, ureteral stents are used (a) in post-endourologicalprocedures to act as a scaffold in the event of ureteral obstructionsecondary to the procedure, (b) following procedures (e.g.,ureteroscopies, endourerotomies, endopyelotomies, etc.) for thetreatment of ureteral strictures and (c) in other instances whereureteral drainage may need to be facilitated, for example, due to theappearance of kidney stones, among other uses.

However, such stents are commonly associated with pain and discomfort inthe bladder and/or flank area after insertion. There are various methodsthat have been employed to reduce the pain associated with such devices.For example, one way by which pain and discomfort may be minimized is tosystemically administer pain-killing drugs to the patient. However,pain-killing drugs are associated with undesirable side effects,particularly with opioid analgesia which are commonly prescribedsystemically for this purpose. Moreover, the subject is typicallyrequired to bear the pain, trauma and/or expense of going to a physicianfor stent removal.

SUMMARY OF THE INVENTION

According to an aspect of the present invention, the present inventionprovides medical devices which contain one or more polymeric regionsthat are at least partially biodisintegrable in bodily fluid. Thesedevices may be implanted or inserted into a subject for treatment ofvarious diseases, disorders and conditions.

An advantage of certain embodiments of the present invention is thatmedical devices may be provided which partially or completelydisintegrate in bodily fluid, in some instances completely vanishingafter the usefulness of the device has been served. For example, thedevices may be disintegrated in some embodiments by urine that is voidedout by a subject, by blood flow, and so forth. In the case of ureteralstents, for instance, such devices may be adapted to partially orcompletely disintegrate after their purpose of providing luminalscaffolding has been served. Pain and irritation associated with thepresence of the device may decrease as the device disintegrates,eventually disappearing along with the device in some embodiments.

Another advantage of certain embodiments of the present invention isthat medical devices may be provided which do not need to be removedfrom the body. For example, in the case of a completely biodisintegrableureteral stent, the subject will avoid the pain, trauma and/or expenseof going to a health care provider for stent removal.

These and other aspects, embodiments and advantages of the presentinvention will become immediately apparent to those of ordinary skill inthe art upon review of the Detailed Description and any Claims tofollow.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a side view of a ureteral stent, in accordance with anembodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A more complete understanding of the present invention is available byreference to the following detailed description of numerous aspects andembodiments of the invention. The detailed description of the inventionwhich follows is intended to illustrate but not limit the invention.

In one aspect, the present invention provides medical devices whichcontain one or more polymeric regions that are at least partiallybiodisintegrable in bodily fluid. The devices may be implanted orinserted into a subject for treatment of various diseases, disorders andconditions.

As used herein, “treatment” refers to the prevention of a disease,disorder or condition, the reduction or elimination of symptomsassociated with a disease, disorder or condition, or the substantial orcomplete elimination of a disease, disorder or condition.

Preferred subjects (also referred to as “patients”) are vertebratesubjects, more preferably mammalian subjects and more preferably humansubjects.

Examples of medical devices benefiting from the present inventioninclude implantable or insertable medical devices, including those thatare implanted or inserted to temporarily act as scaffolding for a bodylumen, for example, ureteral stents, urethral stents, coronary vascularstents, peripheral vascular stents, cerebral stents, biliary stents,tracheal stents, gastrointestinal stents, and esophageal stents.

Particular medical devices benefiting from the present invention includekidney-ureter-bladder (KUB) devices such as ureteral stents. As notedabove, these devices are used in post-endourological procedures toprevent ureteral obstruction secondary to the procedure, for example,(a) following various procedures for the treatment of ureteralstrictures or (b) in other instances where drainage from the kidney tothe bladder may need to be facilitated.

A schematic diagram of such one such stent 10 is illustrated in theFIGURE. The stent 10 is of a tubular construction and has a renalpigtail 12, a shaft 14 and a bladder pigtail 16. The pigtails 12, 16serve to keep the stent 10 in place once positioned by the physician.The stent 10 is further provided with a tapered tip 11, to aidinsertion, and multiple side ports 18 (one numbered) are arranged in aspiral pattern down the length of the stent body, which promotedrainage. During placement, the ureteral stent 10 may be placed over aurology guidewire, through a cystoscope and advanced into position witha positioner. Once the proximal end of the stent is advanced into thekidney/renal calyx, the guidewire is removed, allowing the pigtails 12,16 to form in the kidney and bladder. The stent shown is similar inappearance to the Percuflex® Ureteral Stent (Boston Scientific, Natick,Mass., USA). The Percuflex® Ureteral Stent, however, is formed from abiostable polymeric material (i.e., ethylene vinyl acetate copolymer),whereas the stent 10 is at least partially formed from aurine-disintegrable polymer.

For example, in some embodiments, the ureteral stent may comprise afirst polymeric portion, which occupies the bladder and which is adaptedto biodisintegrate in vivo. The first portion may comprise abiodisintegrable polymer. In these embodiments, the ureteral stent alsocomprises a second polymeric portion, which occupies the kidney and theureter, and which biodisintegrates partially (e.g., because it is formedof a biodisintegratable polymer blended with a biostable polymer),biodisintegrates more slowly than the first portion, or does notbiodisintegrate at all. The second portion may thus comprise abiodisintegrable polymer, a biostable polymer, or both. As indicatedabove, the bladder region is most commonly associated with patient painor irritation after being deployed within a patient. Biodisintegrationof the bladder-occupying portion, which may occur, for example, uponexposure to urine being voided by the patient, will be associated withimproved patient comfort.

In some embodiments of the invention, ureteral stents are provided witha partially biodegradable region (e.g., the bladder portion, the entiredevice, etc.) which comprises a biodisintegrable polymer blended with abiostable polymer. Upon placement in a subject at least part of thebiodisintegrable polymer is removed from the partially biodisintegrableregion, thereby improving patient comfort.

A “polymeric” region is one that contains polymers, for example, from 50wt % or less to 75 wt % to 90 wt % to 95 wt % to 97.5 wt % to 99 wt % ormore polymers. Polymeric regions may correspond to an entire device orto a portion thereof.

By “biodisintegrable” polymer is meant that the polymer undergoesdissolution, degradation, resorption and/or some other in vivodisintegration process (biodisintegration process) over the time periodfor which the medical device is designed to reside in the body.Similarly, by “biostable” is meant that the polymer remainssubstantially intact over the time period for which the medical deviceis designed to reside in the body.

As used herein, “polymers” are molecules containing multiple copies(e.g., from 2 to 5 to 10 to 25 to 50 to 100 to 250 to 500 to 1000 ormore copies) of one or more constitutional units, commonly referred toas monomers. As used herein, the term “monomers” may refer to freemonomers and to those that are incorporated into polymers, with thedistinction being clear from the context in which the term is used.

Polymers may take on a number of configurations, which may be selected,for example, from cyclic, linear and branched configurations. Branchedconfigurations include star-shaped configurations (e.g., configurationsin which three or more chains emanate from a single branch point), combconfigurations (e.g., configurations having a main chain and a pluralityof side chains), dendritic configurations (e.g., arborescent andhyperbranched polymers), and so forth.

As used herein, “homopolymers” are polymers that contain multiple copiesof a single constitutional unit. “Copolymers” are polymers that containmultiple copies of at least two dissimilar constitutional units,examples of which include random, statistical, gradient, periodic (e.g.,alternating) and block copolymers.

As used herein, “block copolymers” are copolymers that contain two ormore polymer blocks that differ in composition, for instance, because aconstitutional unit (i.e., monomer) is found in one polymer block thatis not found in another polymer block. As used herein, a “polymer block”is a grouping of constitutional units (e.g., 5 to 10 to 25 to 50 to 100to 250 to 500 to 1000 or more units). Blocks can be branched orunbranched. Blocks can contain a single type of constitutional unit(also referred to herein as “homopolymeric blocks”) or multiple types ofconstitutional units (also referred to herein as “copolymeric blocks”)which may be provided, for example, in a random, statistical, gradient,or periodic (e.g., alternating) distribution.

Examples of biostable and biodisintegrable polymers include a variety ofhomopolymers and copolymers and may be selected, for example, from oneor more suitable members of the following: polycarboxylic acid polymersand copolymers including polyacrylic acids; acetal polymers andcopolymers; acrylate and methacrylate polymers and copolymers (e.g.,n-butyl methacrylate); cellulosic polymers and copolymers, includingcellulose acetates, cellulose nitrates, cellulose propionates, celluloseacetate butyrates, cellophanes, rayons, rayon triacetates, and celluloseethers such as carboxymethyl celluloses and hydroxyalkyl celluloses;polyoxymethylene polymers and copolymers; polyimide polymers andcopolymers such as polyether block imides and polyether block amides,polyamidimides, polyesterimides, and polyetherimides; polysulfonepolymers and copolymers including polyarylsulfones andpolyethersulfones; polyamide polymers and copolymers including nylon6,6, nylon 12, polycaprolactams and polyacrylamides; resins includingalkyd resins, phenolic resins, urea resins, melamine resins, epoxyresins, allyl resins and epoxide resins; polycarbonates;polyacrylonitriles; polyvinylpyrrolidones (cross-linked and otherwise);polymers and copolymers of vinyl monomers including polyvinyl alcohols,polyvinyl halides such as polyvinyl chlorides, ethylene-vinyl acetatecopolymers (EVA), polyvinylidene chlorides, polyvinyl ethers such aspolyvinyl methyl ethers, polystyrenes, styrene-maleic anhydridecopolymers, vinyl-aromatic-olefin copolymers, includingstyrene-butadiene copolymers, styrene-ethylene-butylene copolymers(e.g., a polystyrene-polyethylene/butylene-polystyrene (SEBS) copolymer,available as Kraton® G series polymers), styrene-isoprene copolymers(e.g., polystyrene-polyisoprene-polystyrene), acrylonitrile-styrenecopolymers, acrylonitrile-butadiene-styrene copolymers,styrene-butadiene copolymers and styrene-isobutylene copolymers (e.g.,polyisobutylene-polystyrene and polystyrene-polyisobutylene-polystyreneblock copolymers such as those disclosed in U.S. Pat. No. 6,545,097 toPinchuk), polyvinyl ketones, polyvinylcarbazoles, and polyvinyl esterssuch as polyvinyl acetates; polybenzimidazoles; ethylene-methacrylicacid copolymers and ethylene-acrylic acid copolymers, where some of theacid groups can be neutralized with either zinc or sodium ions (commonlyknown as ionomers); polyalkyl oxide polymers and copolymers includingpolyethylene oxides (PEO); polyesters including polyethyleneterephthalates and aliphatic polyesters such as polymers and copolymersof lactide (which includes lactic acid as well as d-,l- and mesolactide), epsilon-caprolactone, glycolide (including glycolic acid),hydroxybutyrate, hydroxyvalerate, para-dioxanone, trimethylene carbonate(and its alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and6,6-dimethyl-1,4-dioxan-2-one (a copolymer of poly(lactic acid) andpoly(caprolactone) is one specific example); polyether polymers andcopolymers including polyarylethers such as polyphenylene ethers,polyether ketones, polyether ether ketones; polyphenylene sulfides;polyisocyanates; polyolefin polymers and copolymers, includingpolyalkylenes such as polypropylenes, polyethylenes (low and highdensity, low and high molecular weight), polybutylenes (such aspolybut-1-ene and polyisobutylene), polyolefin elastomers (e.g.,santoprene), ethylene propylene diene monomer (EPDM) rubbers,poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers,ethylene-methyl methacrylate copolymers and ethylene-vinyl acetatecopolymers; fluorinated polymers and copolymers, includingpolytetrafluoroethylenes (PTFE),poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modifiedethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidenefluorides (PVDF); silicone polymers and copolymers; thermoplasticpolyurethanes (TPU); elastomers such as elastomeric polyurethanes andpolyurethane copolymers (including block and random copolymers that arepolyether based, polyester based, polycarbonate based, aliphatic based,aromatic based and mixtures thereof; examples of commercially availablepolyurethane copolymers include Bionate®, Carbothane®, Tecoflex®,Tecothane®, Tecophilic®, Tecoplast®, Pellethane®, Chronothane® andChronoflex®); p-xylylene polymers; polyiminocarbonates;copoly(ether-esters) such as polyethylene oxide-polylactic acidcopolymers; polyphosphazines; polyalkylene oxalates; polyoxaamides andpolyoxaesters (including those containing amines and/or amido groups);polyorthoesters; biopolymers, such as polypeptides, proteins, andpolysaccharides, including fibrin, fibrinogen, collagen, elastin,chitosan, gelatin, starch, glycosaminoglycans such as hyaluronic acid;as well as further copolymers of the above.

In certain embodiments of the invention, medical devices are provided,part or all of which are soluble in aqueous solutions (e.g., at pH'sencountered in the body of a subject, including neutral, mildly basicand mildly acidic pH's). As a result, part or all of such devices (e.g.,an entire ureteral stent, only the distal bladder portion of a ureteralstent, the dissolvable portion of a blend of dissolvable and biostablepolymers, etc.) may be become dissolved after implanting or insertingthe device in a subject and upon exposure to bodily fluids. In theseembodiments, the water soluble regions of the medical devices containone or more dissolvable polymers.

Several water soluble polymers, many of which are also thermoplasticpolymers, are described in U.S. Pat. No. 6,818,283, U.S. Pat. No.6,072,100, U.S. Pat. No. 5,286,415, U.S. Pat. No. 5,229,124, U.S. Pat.No. 6,608,014 and U.S. Pat. App. Pub. No. 2001/0033852. These include,for example, polysaccharide homopolymers and copolymers, polyvinylalcohol homopolymers and copolymers, polyethyloxyazoline homopolymersand copolymers, polyacrylamide homopolymers and copolymers, polyacrylicacid homopolymers and copolymers, polyvinyl pyrrolidone homopolymers andcopolymers such as vinylpyrrolidone/vinyl acetate copolymers (e.g.,Plasdone®, available from International Specialty Products, Wayne, N.J.,USA) and styrene/vinylpyrrolidone copolymers, polyethylene oxidehomopolymers and copolymers including POLYOX polymers produced by UnionCarbide Corp., Bound Brook, N.J., USA, and melt processablepoly(ethylene oxide) modified by grafting of polar vinyl monomers, suchas poly(ethylene glycol)methacrylate and 2-hydroxyethyl methacrylateonto poly(ethylene oxide) as described in U.S. Pat. App. Pub. No.2001/0033852.

Cellulose is a polysaccharide that is a linear polymer of glucose. It isquite plentiful, as it is the major structural constituent of plant cellwalls. Various properties of cellulose, including its solubility inaqueous solutions among others, may be changed by adding entities to thecellulose that comprise functional groups such as ether, ester,hydroxyl, amino, and/or carboxylic acid (carboxyl) groups. These andotherwise modified polysaccharides based on cellulose are referred toherein as cellulose-derived carbohydrates.

Cellulose-derived carbohydrates that are soluble in aqueous solutionsinclude hydroxyalkyl cellulose ethers and alkyl cellulose ethers such ashydroxypropyl cellulose ether and methyl cellulose ether products soldas METHOCEL from Dow Chemical, and thermoplastic, water-solublecellulose derivatives such as those described in U.S. Pat. App. Pub. No.2004/0147737.

Cellulose-derived carbohydrates that are soluble in aqueous solutionsfurther include carboxylated celluloses. As used herein “carboxylatedcelluloses” are cellulose polymers (i.e., polyglucoses) that containcarboxyl functional groups, which are not ordinarily found in cellulose,and may contain other functional groups that are not ordinarily found incellulose as well. Carboxylated celluloses include oxidized celluloses,carboxylated cellulose ethers (e.g., carboxymethylcellulose),carboxylated cellulose esters such as carboxyalkyl and carboxyarylcellulose esters (e.g., cellulose monoesters of maleic acid, succinicacid, or phthalic acid), and oxidized cellulose alkylates (e.g.,oxidized cellulose acetate), among others.

Carboxylated celluloses can be made through various processes includingoxidation of cellulose and cellulose alkylates, etherification ofcellulose, and/or esterification of cellulose, among other techniques.

The predominant reaction of oxidants (e.g., nitrogen dioxide, etc.) withcellulose is reportedly the oxidation to carboxyl groups of the primaryhydroxyl groups that are found on the 6-carbon position of the glucosemonomers in the cellulose. For this reason, oxidized cellulose issometimes referred to as 6-carboxycellulose, although carbon atoms otherthan the 6-carbon may be oxidized. In addition to nitrogen dioxide(dinitrogen tetroxide), further oxidants that have been reported for theoxidation of cellulose include hypohalites, chlorine dioxide,permanganates, peroxides, dichromate-sulfuric acid, hypochlorous acid,gaseous chlorine, peracetic acid, periodic acid, persulfates, chromicacid, and hypochlorous acid. In addition to carboxyl groups and anyunreacted hydroxyl groups, such oxidized celluloses may also containaldehyde, ketone and/or other functionalities, depending on the natureof the oxidant and the reaction conditions used in their preparation.Some of these processes tend to preserve the cellulose in the form offibers whereas other processes tend to break down the cellulose intoparticles of lower aspect ratio.

The carboxyl content of oxidized cellulose can range from less than 1 wt% to 5 wt % to 10 wt % to 15 wt % to 20 wt % up to the theoreticalmaximum of 25.6 wt % where all primary hydroxyl groups in the cellulosehave been oxidized to carboxyl groups, although carboxyl contents ofgreater than 25.6 wt % can also be achieved by oxidizing other locationson the glucose units. Oxidized cellulose has been described as a weakpolyacid with a reported pKa of about 3.6-4.0. It is typically insolublein water but is soluble in mildly alkaline solutions.

U.S. Pat. No. 6,627,749 describes one particular method of preparingoxidized cellulose with different levels of oxidation and in highyields. The method involves treatment of a cellulose source with amixture of phosphoric acid, nitric acid, and sodium nitrite at roomtemperature for a period until the desired level of oxidation (up to25.6%) is achieved. According to this reference, oxidized cellulose withless than 3% carboxylic content serves as a non-degradable drug carrier,whereas oxidized cellulose containing equal to or greater than 3%carboxylic groups is useful as a biodegradable drug carrier.

Other methods of forming carboxylated cellulose involve etherificationand esterification of cellulose. Etherification of cellulose bymonochloroacetic acid yields carboxylated cellulose (i.e., carboxyalkylcellulose, specifically, carboxymethyl cellulose) with relatively highcarboxyl content, and the carboxylated cellulose products produced inthis fashion are typically particles, rather than fibers, if the degreeof substitution (DS) of carboxyl group is higher than 0.3. For furtherinformation, see, e.g., U.S. Pat. No. 6,627,750.

Esterification of cellulose may proceed, for example, by reaction withdicarboxylic acid anhydrides or chlorides, such as succinic anhydride,maleic anhydride, phthalic anhydride, or oxalyl chloride. For example,in U.S. Pat. No. 4,734,239, water-insoluble fibers of cellulosemonoesters of maleic acid, succinic acid, or phthalic acid, which have ahigh absorption ability for water and physiological liquids, areproduced by reacting a solution of activated cellulose and LiCl with acorresponding carboxylic acid anhydride in the presence of anesterification catalyst. The resulting carboxylated cellulose solutionis wet spun into a coagulation agent.

Other processes involve a combination of the above processes. As anexample, V. Kumar et al., “Oxidized cellulose esters: I. Preparation andcharacterization of oxidized cellulose acetates—a new class ofbiodegradable polymers,” J Biomater Sci Polym Ed. 2002; 13(3):273-86report oxidized cellulose acetates, with a carboxylic acid groupcontents of 20 wt %. These are reportedly created by the reaction ofoxidized cellulose having 20 wt % carboxyl content with a mixture ofacetic acid and acetic anhydride in the presence of sulfuric acid as acatalyst. The apparent pKa of the oxidized cellulose acetate is 3.7-3.9.The polymers are practically insoluble in water, but dissolve slowly atpH 7.4 in phosphate buffer solution.

Further information on carboxylated celluloses can be found in U.S. Pat.No. 6,627,750; U.S. Pat. No. 5,414,079; Lihua Zhu et al., “Examinationof Aqueous Oxidized Cellulose Dispersions as a Potential Drug Carrier.I. Preparation and Characterization of OxidizedCellulose-Phenylpropanolamine Complexes,” AAPS PharmSciTech 2004 5 (4)Article 69; Lihua Zhu et al., “Examination of Aqueous Oxidized CelluloseDispersions as a Potential Drug Carrier. II. In Vitro and In VivoEvaluation of Phenylpropanolamine Release From Microparticles andPellets,” AAPS PharmSciTech 2004 5 (4) Article 70(http://www.aapspharmscitech.org); and the Introduction from a thesisentitled “The Limited Oxidation of Cellulose with Nitrogen Dioxide inCarbon Tetrachloride,” submitted by J. R. Parkinson for the degree ofDoctor of Philosophy, Lawrence College, Appleton, Wis., USA, June 1957.

Solubility of carboxylated celluloses may be increased, for example, byincreasing the number of carboxyl groups, by neutralizing some or all ofthe carboxyl groups to form a carboxylated cellulose salt, or both. Inthis regard, the L. Zhu et al. articles above discuss the partialneutralization of oxidized cellulose using NaOH, with reported degreesof neutralization ranging from 0.2 or less to 0.5 or more (0.22 to 0.44were preferred in those articles based on their ability to form aqueousdispersions for complexation with phenylpropanolamine-HCl).

In some embodiments, a soluble polymers such as carboxylated cellulosesmay be admixed with a biostable polymer. As noted in U.S. Pat. No.6,627,750, the compatibility of cellulose with other polymeric materialsmay be improved when carboxylic acid groups are added to the cellulose.

Chitosan is a modified polysaccharide containing randomly distributedβ-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine monomer units.Chitosan is produced commercially by the alkaline N-deacetylation ofchitin, which is a cellulose-like polymer consisting primarily ofunbranched chains of modified glucose, specificallyN-acetyl-D-glucosamine. The degree of acetylation in commercialchitosans generally ranges from 60 to 70 to 80 to 90 to 100% althoughessentially any degree of acetylation is possible. Chitosan is alsopositively charged in acidic to neutral solutions with a charge densitydependent on the pH and the degree of deacetylation. The pka value ofchitosan generally ranges from 6.1 to 7.0, depending on the degree ofdeacetylation. Thus, while substantially insoluble in distilled water,chitosan is generally soluble in dilute aqueous acid (e.g., pH=6.5 orless). M. Fukuda, “Properties of sustained release hot-melt extrudedtablets containing chitosan and xanthan gum,” Int Pharm. 2006 Mar. 9;310(1-2):90-100. Epub 2006 Jan. 18, describe hot-melt extrudedcompositions of chitosan, specifically hot-melt extruded compositionscontaining chitosan and xanthan gum.

Examples of water soluble polymers further include polyvinyl alcohol(PVOH) polymers and copolymers. Polyvinyl alcohols are hydrolysisproducts of polyvinyl acetate or another polyvinyl ester. Polyvinylalcohols, without modification, tend to be non-thermoplastic, generallyhaving decomposition temperatures below their melting points. However,polyvinyl-alcohol-based compositions may be either externally orinternally plasticized so as to exhibit thermoplastic properties. It isknown for example to plasticize PVOH by adding such plasticizers aspolyethylene glycol, glycerol and neopentyl glycol, thereby giving PVOHcompositions thermoplastic properties. Internally plasticized PVOHcopolymers include copolymers of vinyl alcohol and (alkyleneoxy)acrylatesuch as VINEX from Air Products. The physical properties of PVOH,including the strength and water solubility, vary with the degree ofcrystallinity. Specifically, greater crystallinity typically leads togreater strength and lower water solubility. The degree of crystallinityis dependent, for example, on the degree of hydrolysis and the averagemolecular weight of the polymer, the amount of plasticizer, theproduction process (e.g., whether acid or base catalysed). Partiallyhydrolysed PVOH contains residual acetate groups, which reduce theoverall degree of crystallinity of the polymer. Melt processable,pellets of fully hydrolysed PVOH (and plasticizers) are available fromEnvironmental Polymers Group Plc. Annealing a partially or fullyhydrolysed PVOH by an annealing process increases the degree ofcrystallinity of the material and thus reduces its water solubility. Forfurther information regarding polyvinyl alcohol polymers and copolymerssee, e.g., U.S. Pat. No. 5,229,124 and “Thermoplastic Poly (VinylAlcohol) (PVOH),” Primary author: Nigel Hodgkinson and Michael Taylor,Source: Materials World, vol. 8, pp. 24-25, April 2000, published atAzom.com, as well as the references cited therein.

Thus, the in vivo solubility of a medical device or a portion thereofcan be varied by varying the crystallinity of the material, which inturn may be varied by varying the degree of hydrolysis of the polymer,the average molecular weight of the polymer, the amount of additives(e.g., plasticizer, etc.) if any, the production process, the degree ofannealing, and so forth.

As previously noted, examples of polymers for forming the devices of thepresent invention include water soluble polymers and polymers that aresoluble in mildly basic (e.g., carboxylated celluloses) or mildly acidic(e.g., chitosan) aqueous solutions. To the extent that the environmentinto which the device is implanted does not have an ideal pH fordissolution (e.g., because it causes the aqueous soluble polymer todissolve too slowly or too quickly), the pH may be manipulated byincluding a pH-adjusting compound (e.g., acid or base) in the device(e.g., the device may contain one or more polymeric regions thatcomprise one or more polymers and one or more pH-adjusting compounds) orby administering compositions to the subject that change the pH of thein vivo environment where the device is located.

For example, where the device dissolves under mildly alkaline conditionsand dissolves too slowly in the implanted environment, a basic compoundcan be added to the device or a composition may be administered to thesubject to make the environment surrounding the device more basic. Asanother example, where the device dissolves under mildly alkalineconditions and dissolves too quickly in the implanted environment, anacidic compound can be added to the device or a composition may beadministered to the subject to make the environment surrounding thedevice more acidic.

Conversely, where the device dissolves under mildly acidic conditionsand dissolves too slowly in the implanted environment, an acidiccompound can be added to the device or a composition may be administeredto the subject to the subject to make the environment surrounding thedevice more acidic. As yet another example, where the device dissolvesunder mildly basic conditions and dissolves too slowly in the implantedenvironment, a basic compound can be added to the device or acomposition may be administered to the subject to make the environmentsurrounding the device more basic.

Thus, in accordance with one specific embodiment of the invention, aurological device (e.g., a ureteral stent, etc.) is provided whichcomprises a dissolvable polymer having acidic groups (e.g., oxidizedcellulose, etc.) and a basic pH adjusting agent (e.g., an alkali metalhydroxide such as sodium hydroxide, etc.).

In accordance with another specific embodiment of the invention aurological device (e.g., ureteral stent, etc.) is provided whichcomprises a dissolvable polymer having basic groups (e.g., chitosan,etc.) and an acidic pH adjusting agent (e.g., ascorbic acid, etc.).

In instances where one or more devices are placed within the urinarytract, the pH of the environment surrounding the device can be increasedby administering to the subject one or more compositions that alkalinizethe subject's urine. Compositions for alkalinizing urine include one ormore of the following, among others: carbonic anhydrase inhibitors(e.g., acetazolamide, dichlorphenamide or methazolamide), potassiumcitrate, sodium citrate, citric acid, sodium bicarbonate,calcium-containing antacids, and magnesium-containing antacids.

On the other hand, the pH of the environment surrounding the device canbe decreased by administering to the subject one or more compositionsthat acidify the subject's urine. Compositions for acidifying urineinclude one or more of the following, among others: natural productssuch as cranberry juice, inorganic compounds such as ammonium chloride,and organic compounds such as methenamine, methenamine mandelate,methionine, ascorbic acid, mandelic acids, hippuric acid (found incranberry juice), and other organic acids.

Thus compositions may be administered to the subject from the time ofimplantation of a device that is relatively unstable under in vivoconditions to retard dissolution of the medical device in vivo, and suchadministration may be ceased at a later point in time in order to speeddissolution. Conversely, the medical device may be relatively stableunder in vivo conditions, whereas compositions may be administered atthe time of implantation or after a certain time period has elapsed inorder to speed dissolution.

For example, in accordance with specific embodiment of the invention, amethod is provided for increasing the in vivo solubility of a urologicalmedical device that comprises a dissolvable polymer having acidicgroups. The method comprises administering to a subject a compositionthat increases the pH of the subject's urine at a point in time when itis desired to increase the rate of dissolution of the device.

In accordance with another specific embodiment, a method is provided forincreasing the in vivo solubility of a urological medical device thatcomprises a dissolvable polymer having basic groups. The methodcomprises administering to a subject a composition that decreases the pHof the subject's urine at a point in time when it is desired to increasethe rate of dissolution of the device.

In accordance with another specific embodiment, a method is provided fordecreasing the in vivo solubility of a urological medical device thatcomprises a dissolvable polymer having acidic groups. The methodcomprises administering to a subject a composition that decreases the pHof the subject's urine up until at a point in time when it is desired toincrease the rate of dissolution of the device, at which pointadministration of the composition is discontinued.

In accordance with another specific embodiment, a method is provided fordecreasing the in vivo solubility of a urological medical device thatcomprises a dissolvable polymer having basic groups. The methodcomprises administering to a subject a composition that increases the pHof the subject's urine up until at a point in time when it is desired toincrease the rate of dissolution of the device, at which pointadministration of the composition is discontinued.

In some embodiments, devices in accordance with the present inventionare adapted to release one or more therapeutic agents. For example, thedevices of the present invention may contain one or more polymericregions that comprise one or more polymers and one or more optionaltherapeutic agents, among other optional additives.

“Therapeutic agents,” “drugs,” “pharmaceutically active agents,”“pharmaceutically active materials,” and other related terms may be usedinterchangeably herein.

Examples of optional therapeutic agents include those which may serve tolocally suppress pain and discomfort, for example, an agent selectedfrom steroidal anti-inflammatory agents (e.g., cortisone, etc.),non-steroidal anti-inflammatory agents (e.g., ketorolac, etc.), narcoticanalgesic agents (e.g., codeine, morphine, etc.), non-narcotic analgesicagents (e.g., acetaminophen, etc.), anesthetic agents (e.g., novocaine,etc.), antispasmodic agents (e.g., oxybutynin, etc.), or a combinationthereof. See U.S. Pat. App. Pub. No. 2003/0224033 to Li et al. forfurther examples of therapeutic agents.

Where one or more therapeutic agents are present, a wide range oftherapeutic agent loadings can be used, with the therapeuticallyeffective amount varying widely based on a number of factors, but beingreadily determined by those of ordinary skill in the art. Typicalloadings range, for example, from 1 wt % or less to 2 wt % to 5 wt % to10 wt % to 25 wt % or more of the device.

Further optional additives include radio-opacifying agents to facilitateviewing of the medical device during implantation or insertion of thedevice. A radio-opacifying agent typically functions by scatteringx-rays. The areas of the medical device that scatter the x-rays may bedetectable on a radiograph. Among radio-opacifying agents useful in themedical device of the present invention are included bismuth salts suchas bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, bariumsulfate, tungsten, and mixtures thereof, with bismuth salts typicallybeing preferred. Where present, the radio-opacifying agent is typicallypresent in an amount of from about 10% to about 40% (including 10% to15% to 20% to 25% to 30% to 35% to 40%, with 15-30% being more typical).One skilled in the art can readily determine an appropriateradio-opacifying agent content to achieve the desired visibility.

In some embodiments, the devices of the invention are optionallyprovided with an agent to facilitate thermoplastic processing (e.g., aplasticizer).

In some embodiments, the devices of the invention are optionallyprovided with lubricious layers such as water soluble hydrogel layers tofacilitate implantation or insertion of the medical device.

Numerous techniques are available for forming wholly or partiallybiodisintegrable polymeric regions in accordance with the presentinvention.

For example, where the polymeric regions are formed from one or morecomponents that have thermoplastic characteristics (e.g., athermoplastic polymer, due to an additive that renders the compositionthermoplastic, etc.), a variety of standard thermoplastic processingtechniques may be used to form the polymeric regions, includingcompression molding, injection molding, blow molding, spinning, vacuumforming and calendaring, extrusion into sheets, fibers, rods, tubes andother cross-sectional profiles of various lengths, and combinations ofthese processes. Using these and other thermoplastic processingtechniques, entire devices or portions thereof can be made.

Mixing or compounding the one or more polymer(s) and one or moreoptional additives (e.g., pH adjusting agents, therapeutic agents,radio-opacifiers, processing aids such as plasticizers, etc.) duringprocessing may be performed using any technique known in the art. Forexample, a melt may be formed which includes the polymer(s) and one ormore optional agents. A common way of doing so is to apply mechanicalshear to a mixture. Devices for this purpose include, for example,single screw extruders, twin screw extruders, banbury mixers, high-speedmixers, and ross kettles, among others. Once compounded, the materialscan then be processed using any of a variety of thermoplastic processingtechniques such as those described above (e.g., extrusion, molding,casting, etc.).

Among the processing conditions that may be controlled duringthermoplastic processing are the temperature, applied shear rate, andresidence time in the processing device, among others.

Other processing techniques besides thermoplastic processing techniquesmay also be used to form the polymeric regions in accordance with thepresent invention, including solvent-based techniques. Using thesetechniques, a polymeric region can be formed by (a) first providing asolution or dispersion that contains the polymer(s) and any optionalagent(s) and (b) subsequently removing the solvent. The solvent that isultimately selected will contain one or more solvent species, which aregenerally selected based on their ability to dissolve the polymer(s)(and optional agent(s) as well in many embodiments), in addition toother factors, including drying rate, surface tension, etc. Preferredsolvent-based techniques include, but are not limited to, solventcasting techniques, spin coating techniques, web coating techniques,solvent spraying techniques, dipping techniques, techniques involvingcoating via mechanical suspension including air suspension, ink jettechniques, electrostatic techniques, and combinations of theseprocesses.

In some embodiments of the invention, a polymer containing solution(where solvent-based processing is employed) or a polymer melt (wherethermoplastic processing is employed) is applied to a substrate to forma polymeric region. For example, the substrate can correspond to all ora portion of an implantable or insertable medical device to which apolymeric region is applied. The substrate can also be, for example, atemplate, such as a mold, from which the polymeric region is removedafter solidification. In other embodiments, for example, extrusion andco-extrusion techniques, one or more polymeric regions are formedwithout the aid of a substrate. In a more specific example, an entirestent body may be extruded.

In some embodiments, medical devices in accordance with the inventionmay contain multiple polymeric layers, for example, a polymeric devicebody with further layers such as a layer containing an optionalradio-opacifying agent, a layer containing an optional therapeuticagent, and/or a layer on an external surface that provides lubricity.

In one specific example, oxidized cellulose is blended with a base(e.g., sodium hydroxide) and a radio-opacifying agent (e.g., bismuthsubcarbonate) in a corrosion protected twin screw extruder (e.g., onewith a non-corrosive lining on the outside of the screw and on theinside of the barrel to prevent corrosion by the active ingredients inthe extruder). The blend is then extruded into stents (aftercompounding, if desired) of various sizes (e.g., ranging from 5 to 8Fr). The extruded material is cut to length. If desired, the resultingtube may be machined to provide a tapered tip and/or side ports, and thetube may be annealed to create pigtails like the stent of the FIGURE. Alubricious coating may also be provided as desired.

Various aspects of the invention of the invention relating to the aboveare enumerated in the following paragraphs:

Aspect 1. An implantable or insertable medical device for supporting abody lumen, the device comprising oxidized cellulose, at least a portionof the device softening or completely dissolving upon implantation orinsertion into a subject.

Aspect 2. The implantable or insertable medical device of Aspect 1,further comprising a basic compound.

Aspect 3. The implantable or insertable medical device of Aspect 1,wherein the basic compound is an alkali metal.

Aspect 4. The implantable or insertable medical device of Aspect 1,wherein the device is a urological medical device.

Aspect 5. The implantable or insertable medical device of Aspect 1,wherein the device is a ureteral stent.

Aspect 6. The implantable or insertable medical device of Aspect 1,wherein at least a portion of the medical device comprises a blend ofoxidized cellulose and a biostable polymer and wherein that portion ofthe device softens upon implantation or insertion into the subject.

Aspect 7. The implantable or insertable medical device of Aspect 6,wherein the biostable polymer is an ethylene-vinyl acetate copolymer.

Aspect 8. The implantable or insertable medical device of Aspect 1,wherein the device completely dissolves upon implantation or insertioninto a subject.

Aspect 9. The implantable or insertable medical device of Aspect 1,wherein a first portion of the device completely dissolves uponimplantation or insertion into a subject and a second portion does notcompletely dissolve.

Aspect 10. The implantable or insertable medical device of Aspect 9,wherein the device is a ureteral stent having a proximal end and adistal end, and wherein the proximal end completely dissolves and thedistal end does not.

Aspect 11. A ureteral stent comprising a polymeric region whichcomprises a biodisintegrable polymer blended with a biostable polymer,wherein upon placement in a subject, at least a portion of thebiodisintegrable polymer is removed from the device by urine beingvoided by the subject thereby softening the polymeric region.

Aspect 12. The ureteral stent of Aspect 11, wherein the biodisintegrablepolymer is a water soluble polymer.

Aspect 13. The ureteral stent of Aspect 11, wherein the polymeric regioncomprises oxidized cellulose blended with a ethylene-vinyl acetatecopolymer.

Aspect 14. The ureteral stent of Aspect 11, wherein the regioncorresponds to the proximal end of the stent.

Aspect 15. The ureteral stent of Aspect 11, wherein the regioncorresponds to the entire stent.

Aspect 16. A ureteral stent having a proximal end and a distal end,wherein the proximal end of the stent comprises a biodisintegrablepolymer and completely biodisintegrates upon placement in a subject,wherein the distal end of the stent comprises a biostable polymer, abiodisintegrable polymer, or both, and wherein the distal end of thestent remains intact in vivo, partially biodisintegrates in vivo, orcompletely biodisintegrates in vivo at a slower rate than the rate atwhich the proximal end dissolves.

Aspect 17. The ureteral stent of Aspect 16, wherein the biodisintegrablepolymer is a water soluble polymer.

Aspect 18. The ureteral stent of Aspect 17, wherein the water solublepolymer is oxidized cellulose.

Aspect 19 The ureteral stent of Aspect 16, the distal end of the stentcomprises an ethylene-vinyl acetate copolymer and remains intact invivo.

Aspect 20. A ureteral stent comprising (a) a dissolvable polymercomprising acidic or basic groups and (b) a pH modifying agent, whereinthe pH modifying agent is a base where the polymer comprises acidicgroups and wherein the pH modifying agent is an acid where the polymercomprises basic groups.

Aspect 21. The ureteral stent of Aspect 20, wherein the polymercomprises carboxyl groups.

Aspect 22. The ureteral stent of Aspect 20, wherein the base is analkali metal hydroxide.

Aspect 23. The ureteral stent of Aspect 20, wherein the polymercomprises amino groups.

Aspect 24. The ureteral stent of Aspect 20, wherein the acid is ascorbicacid.

Aspect 25. A method comprising administering to a subject a compositionthat alters the pH of the subject's urine, the subject having insertedor implanted therein a urological medical device that comprises adissolvable polymer, wherein the composition either slows or acceleratesthe dissolution of the dissolvable polymer.

Aspect 26. The method of Aspect 25, wherein the dissolvable polymercomprises acidic groups and wherein the composition increases the pHthereby accelerating the dissolution of the dissolvable polymer.

Aspect 27. The method of Aspect 25, wherein the dissolvable polymercomprises acidic groups and wherein the composition decreases the pHthereby slowing the dissolution of the dissolvable polymer.

Aspect 28. The method of Aspect 25, wherein the dissolvable polymercomprises basic groups and wherein the composition decreases the pHthereby accelerating the dissolution of the dissolvable polymer.

Aspect 29. The method of Aspect 25, wherein the dissolvable polymercomprises basic groups and wherein the composition increases the pHthereby slowing the dissolution of the dissolvable polymer.

Aspect 30. The method of Aspect 25, wherein the urological medicaldevice is a ureteral stent.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

The invention claimed is:
 1. A method of treating a subject, comprising:administering to the subject a composition that alters the pH of thesubject's urine, said subject having inserted or implanted therein aurological medical device that comprises a first polymeric portioncomprising a dissolvable polymer and a second polymeric portioncomprising a non-dissolvable polymer, wherein the compositionaccelerates the dissolution of said dissolvable polymer.
 2. The methodof claim 1, wherein said dissolvable polymer comprises acidic groups andwherein the composition increases the pH thereby accelerating thedissolution of said dissolvable polymer.
 3. The method of claim 1,wherein said dissolvable polymer comprises acidic groups and wherein thecomposition decreases the pH thereby slowing the dissolution of saiddissolvable polymer.
 4. The method of claim 1, wherein said dissolvablepolymer comprises basic groups and wherein the composition decreases thepH thereby accelerating the dissolution of said dissolvable polymer. 5.The method of claim 1, wherein said dissolvable polymer comprises basicgroups and wherein the composition increases the pH thereby slowing thedissolution of said dissolvable polymer.
 6. The method of claim 1,wherein said urological medical device is a ureteral stent.
 7. Themethod of claim 1, wherein the first polymeric portion of the urologicalmedical device is disposed within a bladder of the subject.
 8. Themethod of claim 1, wherein the second polymeric portion of theurological medical device is disposed within a ureter or kidney of thesubject.
 9. The method of claim 1, wherein the first polymeric portioncompletely dissolves following administration of said composition. 10.The method of claim 1, wherein the first polymeric portion partiallydissolves following administration of said composition.
 11. A method oftreating a subject, comprising: administering to the subject acomposition that alters the pH of the subject's urine, said subjecthaving inserted or implanted therein a urological medical device thatcomprises a first polymeric portion comprising a dissolvable polymer anda second polymeric portion comprising a partially dissolvable polymer,wherein the composition accelerates the dissolution of said dissolvableand partially dissolvable polymers.
 12. The method of claim 11, whereinthe dissolvable polymer of the first polymeric portion dissolves moreslowly than the partially dissolvable polymer of the second polymericportion.
 13. The method of claim 11, wherein said dissolvable andpartially dissolvable polymers comprise acidic groups and wherein thecomposition increases the pH thereby accelerating the dissolution ofsaid dissolvable and partially dissolvable polymers.
 14. The method ofclaim 11, wherein said urological medical device is a ureteral stent.15. The method of claim 11, wherein the first polymeric portion of theurological medical device is disposed within a bladder of the subject.16. The method of claim 11, wherein the second polymeric portion of theurological medical device is disposed within a ureter or kidney of thesubject.
 17. The method of claim 11, wherein the first polymeric portioncompletely dissolves following administration of said composition. 18.The method of claim 11, wherein the first polymeric portion partiallydissolves following administration of said composition.